tbuckley/cabot-search huggingface dataset:
Abstract 1050: Non-invasive detection of circulating mRNA markers in diseases of the colon and rectum
Authors: Veronika Vymetalkova, Anna Siskova, Pavel Vodicka, Jiri Jungwirth, Jan Bruha
Journal: Cancer Research (2023)

Abstract Colorectal cancer (CRC) is a worldwide health burden with nearly 1.2 million new cases expected each year globally. When CRC is identified early, there is a five-year survival rate of about 90% but it drops to near 12% once there are distant metastases. Early detection of colorectal adenoma is warranted as it represents the precancerous lesion of CRC. The removal of colorectal adenoma can effectively prevent the subsequent development of CRC. The only preventive strategy is to undergo appropriate endoscopic surveillance and early detection of adenoma or CRC In this study, we focused on the transcriptome profile in patients with colon adenomas, incident colorectal cancer (CRC) and in the healthy population. MRNA transcripts were, in addition to tissues, isolated from the plasma and stool. Plasma and stool analyses should reveal potential mRNA signatures capable of non-invasive determination of the average individual risk of predisposition to adenomas or CRCs. Relevant plasma/stool mRNA will be further validated in another group of individuals with similar clinical characteristics and analyzed in relation to diet and lifestyle factors. For patients with CRC, plasma and stool specimens are collected repeatedly to reveal whether the transcripts identified by us will decrease or diminish in CRC patients after successful surgery. We hypothesize that altered mRNA signatures in plasma and stool may serve as a robust, powerful non-invasive and sufficiently sensitive tool in the early detection of adenomas or CRCs. The bioinformatic analysis is currently running and the results will be presented during the meeting. The long-term significance of the project lays on improvement of the therapy efficacy in colon cancer patients. Supported by grant GACR 22-05942S and by the Ministry of Health of the Czech Republic, grant nr. NU22J-03-00033. Citation Format: Veronika Vymetalkova, Anna Siskova, Pavel Vodicka, Jiri Jungwirth, Jan Bruha. Non-invasive detection of circulating mRNA markers in diseases of the colon and rectum [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1050.
Abstract 5320: The RenMice™ HiTS (Hyperimmune target specific) Platform facilitates identification of novel therapeutic antibodies for challenging targets
Authors: Xiaoqian Zhang, Shufang Fu, Shujin Zhang, Xin Ji, Li Hui, James Jin, Jing Zhang
Journal: Cancer Research (2023)

Abstract In recent years, an increasing number of therapeutic antibodies have shown to be effective for the treatment of cancer and other diseases. However, limitations in the traditional discovery process, including immune tolerance of highly homologous genes, challenges with antibody sequence humanization, clone selection, and model selection for drug efficacy and safety evaluation, often hinder the process of identifying new therapeutic antibodies. The RenMice™ HiTS (Hyperimmune Target Specific) Platform is a library of chromosome engineered mice with fully human immunoglobulin variable domains replacing the mouse loci, each with a specific drug target gene knocked out. These mice are designed to establish robust immune responses and generate antibodies that bind to more epitopes of the target protein, including conserved domains. The platform is ideal for challenging targets, such as proteins with high homology across species, or multi-pass transmembrane proteins (e.g. GPCRs/ion channels). Here, we show that the platform can be used to generate antibodies that cross-react with multiple species, like human, monkey, dog, and mouse targets, by immunizing with both human and mouse or dog antigen. We provide examples for newer campaigns, including species cross-reactivity and internalization of novel antibodies targeting NECTIN-4, and high-throughput in vivo efficacy screening of novel anti-PD-1 antibodies in wild-type mice. In the future, we will evaluate the preliminary toxicity of these cross-reactive antibodies in preclinical animal models. Thus, selection of the best antibody candidate based on in vivo efficacy and safety allows for a streamlined and successful preclinical phase. In conclusion, the RenMice™ HiTS platform facilitates the generation of developable antibodies that recognize novel epitopes and challenging targets. Citation Format: Xiaoqian Zhang, Shufang Fu, Shujin Zhang, Xin Ji, Li Hui, James Jin, Jing Zhang. The RenMice™ HiTS (Hyperimmune target specific) Platform facilitates identification of novel therapeutic antibodies for challenging targets. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5320.
Abstract 4873: Pimavanserin suppresses glioblastoma progression by modulating the Akt/FOXO/Bim signaling axis
Authors: Manas Yogendra Agrawal, Sharavan Ramachandran, Carson Zabel, Sanjay K. Srivastava
Journal: Cancer Research (2023)

Abstract Glioblastoma multiforme (GBM) is a highly aggressive grade IV malignant brain tumor with an average survival time of around 15 months; and a 5-year survival rate of 5%. Drug resistance, blood brain barrier (BBB) impermeability, and drug toxicity are some caveats in treating this malignancy. Current chemotherapeutic agents fail to address these challenges. In this study, we aim to repurpose an FDA-approved anti-psychotic agent Pimavanserin Tartrate (PVT), for the treatment of GBM and further delineate its mechanism. To unravel the oncolytic effects of PVT, cytotoxicity assay on several human (SF268, SF188, SF295, U251) and murine (CT2A-Luc) GBM cell lines was performed. Our results demonstrate that PVT inhibited the growth of various GBM cells with IC50 ranging 5 to 8 µM, contrary to Temozolomide (TMZ), a standard care therapy which has an IC50 ranging 600 to 1,300 µM after 48- and 72-hours of treatment. Moreover, PVT treatment enhanced the activity of TMZ when given in combination. Pro-apoptotic proteins such as cleaved caspase-3 and Bax were upregulated by PVT treatment as evaluated confirming apoptosis to be the mode of cell death. The apoptotic cell population increased in a dose-dependent fashion, for example, 10µM PVT exhibited 70% increase in apoptosis as observed in the annexin assay. PVT treatment suppressed the phosphorylation of PI3K and Akt, and increased the expression of FOXO proteins, which are the negative downstream regulators of Akt. FOXO proteins translocate to the nucleus leading to the enhanced transcription of Bim, a pro-apoptotic protein resulting in apoptosis. Oral administration of 10mg/kg PVT significantly suppressed the growth of intracranially implanted GBM tumors without any other organ toxicity. Our observations provide a robust foundation for PVT’s anti-cancer efficacy against GBM by modulating Akt/FOXO/Bim pathway. Citation Format: Manas Yogendra Agrawal, Sharavan Ramachandran, Carson Zabel, Sanjay K. Srivastava. Pimavanserin suppresses glioblastoma progression by modulating the Akt/FOXO/Bim signaling axis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4873.
Abstract 1457: PDEF restricts prostate cancer cellular plasticity in part by modulating YAP1/TAZ-TEAD transcriptional network
Authors: Hari K. Koul, Praveen K. Jaiswal, Suman Mohajan, Mousa Vatanmakanian, Fengtian Wang, Sweaty Koul
Journal: Cancer Research (2023)

Abstract Background: The Hippo TEAD-transcriptional regulators YAP1 and TAZ play essential role in cancer cell growth and metastasis. However, the function of YAP1 and TAZ in prostate cancer is not well characterized. We discovered that expression of PDEF is decreased during prostate cancer progression and re-expression of PDEF limits prostate cancer metastasis in part by promoting luminal epithelial phenotype, but mechanisms of PDEF action are not completely understood. In the present study, we evaluated the effects of the SPDEF on YAP1/TAZ levels and expression of YAP1/TAZ regulated genes in prostate cancer (PCa) cells. We also evaluated expression of SPDEF, YAP1, TAZ and YAPTAZZ-Tead regulated genes in clinical cohorts of prostate cancer patients. Material &amp; Method: Prostate cancer (PC3 and DU145) cells were transfected with PDEF or respective vector control. shRNA was used to knock down SPDEF in AR positive and androgen responsive LNCaP cells. Protein levels were analyzed by western blotting. Gene expression was monitored by microarray analysis/RNA seq and confirmed by RTPCR assays. Cell migration and invasion were measured by scratch wound healing and by trans well migration though Matrigel assays respectively. We analyzed publicly available gene expression data in several prostate cancer cohorts. Results: We observed that the two well-characterized metastatic PCa cells (PC3 and DU145 cells) express both YAP1 and TAZ, but do not express SPDEF. Expression of PDEF in PC3 and DU145 cells resulted in an increased phospho-YAP1 and phospho-TAZ protein levels and inhibition of YAP1/TAZ target genes, as compared to the respective vector control, directly demonstrating that PDEF plays a critical role in modulating YAP1/TAZ-TEAD transcriptional activity, and by extension in the regulation of the Hippo pathway. Analysis of publicly available PCa data sets revealed a significant increase in TAZ mRNA levels in prostate cancer tissues as compared to normal prostate tissues (p=4.95E-08). Furthermore, we also found a significant gradual increase in TAZ mRNA expression and concomitant decrease in YAP1 mRNA during disease progression and metastasis and in neuroendocrine PCa. Conclusions: Taken together these data suggest that SPDEF limits prostate cancer metastasis in part by targeting YAP1/TAZ driven transcriptional output. Citation Format: Hari K. Koul, Praveen K. Jaiswal, Suman Mohajan, Mousa Vatanmakanian, Fengtian Wang, Sweaty Koul. PDEF restricts prostate cancer cellular plasticity in part by modulating YAP1/TAZ-TEAD transcriptional network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1457.
Abstract 1877: Tripokin: potential best-in-class for tumor targeted interleukin-2 (IL2) potentiated by tumor necrosis factor (TNF)
Authors: Eleonora Prodi, Riccardo Corbellari, Mattia Matasci, Dario Neri, Roberto De Luca
Journal: Cancer Research (2023)

Abstract Among the different pharmacological approaches for cancer treatment, antibody-cytokine fusion proteins (also called “immunocytokines”) represent an emerging class of biopharmaceutical products, capable of boosting the immune system to attack tumor cells as a result of a selective accumulation of pro-inflammatory molecules at the site of disease. When used as single agents, immunocytokines are often not able to cure mice and patients. However, it has been shown by our group that the combination of IL2- and TNF- based products was able to completely eradicate tumors in mouse models and to induce complete responses in cancer patients. We have previously described a novel class of immunocytokine products, termed “potency-matched dual cytokine antibody fusion proteins”, consisting of a tumor-targeting antibody (the F8 antibody, specific to the alternatively spliced EDA domain of fibronectin), simultaneously fused to both IL2 and TNF. To match biological activity of the two payloads a single-point mutation was inserted in the TNF sequence and the resulting product, named IL2-F8-TNFmut was able to selectively localize to tumors with excellent tumor-to-organ ratios and it was found to completely eradicate soft-tissue sarcomas in immunocompetent mice, which did not respond to standard chemotherapy. Moreover, the immunocytokine was able to induce complete responses in a variety of mouse models of cancer. The therapeutic activity was further improved when IL2-F8-TNFmut was used in combination with immune checkpoint inhibitors. At the mechanistic level we observed that the anticancer activity was completely abrogated when CD4+ and CD8+ T cells were depleted, while the contribution of NK cells was negligible. We now report the generation of a new potency-matched dual cytokine antibody fusion protein, named Tripokin based on the L19 antibody, specific to the alternatively spliced EDB domain of fibronectin. Compared to the previous product, Tripokin showed a favorable pharmacokinetic profile in monkey, an excellent localization to neoplastic lesions in mice and was easier to formulate for further clinical applications. When tested in tumor bearing mice, Tripokin revealed a superior anti-cancer activity compared to other IL2-based products.The results obtained in this work provided a rationale for future clinical translation activities using Tripokin as potential best-in-class tumor targeted IL2 product. Citation Format: Eleonora Prodi, Riccardo Corbellari, Mattia Matasci, Dario Neri, Roberto De Luca. Tripokin: potential best-in-class for tumor targeted interleukin-2 (IL2) potentiated by tumor necrosis factor (TNF) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1877.
Abstract 2507: Chronic stress promotes tumor progression and metastasis through the tumor microenvironment in triple-negative breast cancer
Authors: Chao Zhang, Lizhong Wang, Runhua Liu
Journal: Cancer Research (2023)

Abstract Background: Breast cancer is the most common cancer diagnosed in American women. Triple-negative breast cancer (TNBC) is three times more likely to end in death than other breast cancer subtypes and disproportionately affects young African American women. Chronic stress as a risk factor promotes tumor progression, but its role in TNBC progression and metastasis remains elusive. Methods: In this study, mice were implanted with 4T1-luciferase cells in the tibia or the fourth mammary pad of BALB/c mice and NSG mice. After four weeks of restraining inducing chronic stress and (or) β-adrenergic receptor inhibitor treatment, the impact of chronic stress on the progression and metastasis of tumor, tumor microenvironment was assessed. Results: Our results showed that chronic stress facilitated tumor progression and metastasis in both BALB/c mice and NSG TNBC mice models. In contrast, chronic stress reduced the number and function of tumor-infiltrating TCD8+ cells but increased the expression of the β2-adrenergic receptor of TCD8+ cells in the TNBC tumor microenvironment (TME) of BALB/c mice. Interestingly, chronic stress increased the density of neuron fiber in the TME of both BALB/c and NSG TNBC mice. Notably, the treatment of Propranolol (Prop, a β1- and β2-adrenergic receptor inhibitor) significantly decreased the tumor burden and metastasis of both BALB/c mice and NSG TNBC mice model. Accompany by recovering the function and number of TCD8+ cells in the TME of BALB/c mice. Conclusion: Our study indicates that chronic stress promotes TNBC progression and metastasis by regulating the tumor-immune network in the TME. Citation Format: Chao Zhang, Lizhong Wang, Runhua Liu. Chronic stress promotes tumor progression and metastasis through the tumor microenvironment in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2507.
Abstract SY33-02: Novel molecular mechanisms of lung cancer plasticity and targeting lung squamous cell carcinoma
Authors: Cecil Han
Journal: Cancer Research (2023)

Abstract Lung cancer is marked by a high degree of genetic and histopathological heterogeneity. Lineage plasticity, the ability of cells to transform from one cell type to another, has been associated with intratumoral heterogeneity and therapeutic resistance. The molecular drivers and mechanisms of cancer cell plasticity and histological transdifferentiation of lung cancer are largely unknown. A deubiquitinating enzyme, Ubiquitin-Specific Peptidase 13 (USP13), is frequently amplified at chromosome 3q.26 amplicon in lung squamous cell carcinoma. USP13 knock-in overexpressing mouse model was crossed with KrasLSL-G12D; Trp53fl/fl (KP) mouse to generate KrasLSL-G12D; Trp53fl/fl; Usp13LSL (KPU) mouse model. Intratracheal administration of adenovirus expressing Cre recombinase to the lung of the KPU mouse developed aggressive lung tumors and a shortened survival compared to the KP mouse model. Importantly, while the KP mice developed lung adenocarcinoma, 100% of KPU mice developed lung squamous cell carcinoma. The squamous cell carcinoma of the KPU mice faithfully mimicked the molecular signatures, cellular pathways, and tumor microenvironments of human lung squamous cell carcinoma. Delivery of cell type-restricted viruses to the lungs further identified bronchiolar secretory club cells as the predominant cell-of-origin of KPU-induced lung squamous cell carcinoma. USP13 altered the levels of TTF-1 and c-Myc in club cells of the airway and reinforced the fate of CC10+ club cells to squamous carcinoma development instead of adenocarcinoma. USP13 directly acted on the K48-linked ubiquitination of c-Myc and increased the protein stability of c-Myc in human lung cancer cells. Overexpression of USP13 increased the half-life of c-Myc while inhibiting USP13 deubiquitinase activity decreased the c-Myc protein level. USP13 upregulated the expression of squamous lineage markers (Sox2, CK5, P40) in the primary mouse and advanced human lung cancer cells. Our findings revealed that USP13 promotes the lineage plasticity of origin-of-cells of the lung and drives transdifferentiation to squamous cell carcinoma. Finally, our study suggests the critical role of USP13 in unlocking the phenotypic plasticity of lung cancer, which may lead to novel therapeutics targeting lung cancer. Citation Format: Cecil Han. Novel molecular mechanisms of lung cancer plasticity and targeting lung squamous cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY33-02.
Abstract 4673: Therapeutic potential of polatuzumab vedotin for the treatment of diffuse large B-cell lymphoma
Authors: Hui Qi, Fuyang Wang, Bingrui Han, Xiaomin Wang, Xiangnan Qiang, Zhixiang Zhang, Qiangyang Gu
Journal: Cancer Research (2023)

Abstract Background Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Although most patients can be cured with R-CHOP, up to one-third of them relapses with a dismal outcome in most cases. Numerous approaches have been attempted to improve the treatment outcomes with R-CHOP. Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b, which is ubiquitously expressed on over 90% of B-cell NHL malignancies, including DLBCL. To determine the potential of polatuzumab vedotin as a therapeutic agent, we evaluate its potency across a series of DLBCL patient derived xenograft (PDX) models. Method We established and characterized a series of DLBCL lymphoma PDX models. Eight DLBCL PDX models were selected for polatuzumab vedotin efficacy study, of which three are GCB DLBCL. Gene expression analysis of these lymphoma PDX models was performed using an Illumina NovaSeq 6000 system following Illumina-provided protocols for 2 × 150 paired-end sequencing. The expression status of CD79b on these DLBCL PDX models was also evaluated by IHC. Conclusion Our data showed that a single dose of polatuzumab vedotin at just 2 mg/kg could reached a comparable effect with R-CHOP and no significant body weight loss was observed. Our result showed that there is no apparent correlation between polatuzumab vedotin responses (TGI) and the CD79b expression (IHC Score). Although polatuzumab vedotin demonstrated encouraging activity in the treatment of DLBCL, some of the PDX models are also resistant to polatuzumab vedotin treatment. To further investigate the molecular parameters of the relative sensitivity of polatuzumab vedotin. Gene expression profiling of those PDX models and their sensitivity to polatuzumab vedotin were conducted, we found that the expression level of BCL-XL was correlated with reduced sensitivity to polatuzumab vedotin. Citation Format: Hui Qi, Fuyang Wang, Bingrui Han, Xiaomin Wang, Xiangnan Qiang, Zhixiang Zhang, Qiangyang Gu. Therapeutic potential of polatuzumab vedotin for the treatment of diffuse large B-cell lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4673.
Abstract 6514: Liquid biopsy for lung cancer based on extracellular vesicles
Authors: Juan P. Hinestrosa, Harmeet Dhani, Jean M. Lewis, Gregor K. Schroeder, Heath I. Balcer, Razelle Kurzrock, Paul Billings
Journal: Cancer Research (2023)

Abstract Background Liquid biopsy approaches for lung cancer are becoming increasingly common for diagnosis, prognosis, and management of the disease. Of the Approximately 236K new lung cancer cases that will be diagnosed in 2023, over 70% of those will be regional or distant with diminished chances of curative resection. Therefore, highly sensitive and specific approaches for early detection are key for mortality reduction. Extracellular vesicles (EVs), a new class of blood-based cell-free biomarker, can be informative for the diagnosis of lung cancer at its earliest stages. Methods A case-control cohort of blood plasma samples from 146 pathologically confirmed lung cancer cases (stage I = 90, II = 42, III = 14; median age = 63 yrs.) and 491 controls (median age = 58 yrs) was used in this study. EVs were isolated using a proprietary technology and the EV protein cargo was analyzed via immunoassay. A machine learning engine was employed to determine the most informative biomarkers and algorithm for differentiation between cases and controls in a detection setting. Results Using a stratified cross-validation approach, we found a biomarker signature that yielded an AUC of 0.966 (95% CI: 0.949 - 0.979) with an overall sensitivity of 91.1% (CI: 85.4% - 94.7%) at a specificity of 91.0% (CI: 88.2% - 93.3%). By stage, the following sensitivities were obtained: stage I: 92.2%, stage II: 88.1%, stage III: 92.8%. The algorithm developed includes 13 EV-protein biomarkers using the adaptive boosted tree methodology. Conclusions Our pilot study demonstrates utility of a blood-based approach that can detect lung cancer at early stages, when treatment can be more effective. By combining multiple EV protein signatures, it is possible to achieve high sensitivity and specificity. Independently collected cohorts including confounding conditions, such as benign lung nodules and COPD, are being evaluated for validation purposes to improve performance in clinical settings. Citation Format: Juan P. Hinestrosa, Harmeet Dhani, Jean M. Lewis, Gregor K. Schroeder, Heath I. Balcer, Razelle Kurzrock, Paul Billings. Liquid biopsy for lung cancer based on extracellular vesicles. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6514.